P451: PRMT2: AN ANTI-INFLAMMATORY EPIGENETIC FACTOR INVOLVED IN ACUTE MYELOID LEUKEMIA AGGRESSIVENESS
Authors: C. Sauter, J. Simonet, C. Fournier, M. Mounier, M. Rebourgeon, L. Brignoli, A. Aznague, A. Largeot, Y. Hérault, G. Sauvageau, F. Guidez, M. Callanan, J.-N. Bastie, L. Delva, R. Aucagne
Journal: HemaSphere (2022)

Background: Protein Arginine Methyltransferases (PRMTs) are epigenetic factors involved in several cellular processes including regulation of gene expression through methylation of histone tails. Overexpression or overactivity of the two major PRMTs (1 and 5) have been previously identified in Acute Myeloid Leukemia (AML) patients and their biological or pharmacological inhibition leads to a decreased leukemia progression in mice (PRMT1, 4, 5). Among the nine members of this protein family, PRMT2 has been less well characterized. It has been shown to be overexpressed in glioblastoma and is responsible for the H3R8me2a epigenetic mark leading to transcription activation of target genes. In addition, PRMT2 has also been demonstrated to have a role in the inflammatory pathway but its effect is not fully understood yet. Moreover, it is well known that severe chronic inflammation can contribute to the development of certain cancers. Exacerbated inflammatory responses and aberrant myeloproliferation are thus interconnected. Aims: We are investigating the role of PRMT2 in the development of AML and we aim to discover its precise role in the control of inflammatory processes. Methods: We used a PRMT2 knockout mouse model (Prmt2KO), AML patient cohorts of Dijon (Dijon university hospital, France) and Montréal (IRIC, QC, Canada). We also generated a knockout human AML HL-60 cell line using the CRISPR-Cas9 system and a HL-60 cell line overexpressing PRMT2 through the use of a Citrine-tagged fusion protein. Results: Prmt2KO mice do not exhibit difference in bone marrow progenitor or mature cell populations compared to wild type mice, indicating that PRMT2 has little or no influence in the hematopoietic stem cell maintenance. In contrast, we observed that Prmt2KO bone marrow-derived macrophages (BMDM) are more sensitive to lipopolysaccharides (LPS) stimulation and express higher levels of pro-inflammatory cytokine mRNA, suggesting a role of PRMT2 in the negative regulation of the inflammatory processes. Analysis of datasets from a cohort of 371 AML patients (Guy Sauvageau, Leucegene project, IRIC, Montréal, QC, Canada) reveals that patients with a lower PRMT2 expression display a worse survival rate compared to patients with a higher PRMT2 expression. Gene Set Enrichment Analysis of this cohort show that PRMT2 is involved in the inflammatory response signaling pathway, thus confirming our hypothesis. In a cell model we show that PRMT2 knockout cells exhibit higher levels of phosphorylated STAT3 protein compared to wild type cells after LPS stimulation. PRMT2 could therefore be involved directly or indirectly in the STAT3 pathway by preventing its phosphorylation and activation. Ongoing transcriptomic and epigenetic studies could provide new clues for better understanding the role of PRMT2 in an inflammatory context in AML and the association between inflammation and leukemogenesis. Summary/Conclusion: Taken together, our data suggest that PRMT2 has an anti-inflammatory effect in mice and AML patients with a low PRMT2 expression inducing a higher inflammatory phenotype, thus resulting to worse overall survival. PRMT2 could be involved in the STAT3 signaling pathway by preventing its activation leading to increased inflammation.